SUMMARY/ABSTRACT Stimulant abuse is a serious public health problem with untold medical, societal, and economic impact worldwide. Despite decades of research into the neurobiology of drug abuse, there are no FDA-approved pharmacotherapies for stimulant abuse. One strategy to reduce the time required to get candidate medications into the clinic is to repurpose drugs, already approved by the FDA for other indications, to treat stimulant abuse, and one strategy to improve the therapeutic effectiveness of a drug is to administer it in combination with second drug with a complimentary mechanism of action. We and others have shown that drugs that block the effects of DA (buspirone [Buspar]; a DA D2-like [D2, D3, & D4] receptor antagonist, FDA-approved for treating anxiety) or modulate DA transmission (lorcaserin [Belviq]; a serotonin [5-HT]2C receptor agonist, FDA-approved for treating obesity) attenuate the reinforcing and/or relapse-related effects of stimulants such as cocaine in animals. Based on very promising pilot studies in male and female rhesus monkeys, we hypothesize that a combination therapy comprising fixed-doses of drugs that target both pre- (lorcaserin) and post- (buspirone) synaptic regulators of DA neurotransmission will have a therapeutic effect (e.g., decrease in drug-taking) that is greater than the effect of either drug alone (i.e., supra-additive interaction). Our preliminary data support this hypothesis and suggest that combining buspirone with lorcaserin will yield a highly translatable and novel approach to treat stimulant abuse. Studies under Aim 1 test the hypotheses that mixtures of drugs targeting pre- (lorcaserin) and post- (buspirone) synaptic regulators of DA neurotransmission result in a supra-additive inhibition of the reinforcing (progressive ratio and cocaine-food choice) and relapse-related (reinstatement) effects of cocaine, and that these effects differ as a function of sex (e.g., females being less sensitive to buspirone alone, but more sensitive to lorcaserin:buspirone mixtures). Aim 2 tests the hypotheses that the cardiovascular and locomotor effects of lorcaserin and buspirone are not altered when combined in a mixture, and that mixtures of lorcaserin and buspirone do not exacerbate, and may blunt, the cardiovascular effects of cocaine; these effects are not expected to differ as a function of sex. The proposed studies build on compelling preliminary data and test the novel hypothesis that a combination therapy comprising fixed-doses of FDA-approved drugs that target pre-synaptic (5-HT2C receptors; lorcaserin) and post-synaptic (DA D3 receptors; buspirone) regulators of DA neurotransmission are more potent and/or effective at reducing the reinforcing and relapse-related effects of cocaine than would be expected based on the effect of either drug alone (i.e., a supra-additive interaction), without also exacerbating the cardiovascular effects of cocaine. These studies will not only provide new information (within 4 years) about the effects of drug mixtures targeting 5-HT2C and DA D3 receptors, but because lorcaserin and buspirone are already approved by the FDA for use in humans, these results will be highly translatable to the clinic, significantly reducing the time and cost required to determine the effectiveness of mixtures of lorcaserin and buspirone to treat cocaine abuse.